FDA Panel Has No New Echo Contrast Agent Conclusions

W﻿ASHINGTON -- An FDA advisory committee met Monday to decide whether the black box warning on microbubble contrast agents used in echocardiography is too strict, but came to little agreement over whether the box should be removed.

The panel spent the day reviewing data on two contrast agents for use with echocardiograms -- perflutren lipid microspheres (Definity) and perflutren protein-type A microspheres (Optison) -- the safety of which was called into question beginning in 2007, when the FDA became aware of patients who died from cardiovascular collapse or a hypersensitivity reaction after receiving Definity or Optison.

Those reports led the FDA to issue a black box warning for Definity and Optison in 2008 giving them a contraindication in acute cardiopulmonary syndromes, QT prolongation, severe pulmonary hypertension, and acute decompensated heart failure.

But many in the echocardiography community said the black box was too restrictive and that the agents could be safely used, even in sick patients.

FDA documents released in advance of the meeting suggested that the agents might pose problems, especially in women. But the majority of panelists on FDA's Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee agreed that the black box warning was too harsh for ultrasound agents that carry so little risk.

GE Healthcare, the company that makes Optison, said in its briefing documents that serious complications from ultrasound imaging agents are rare, occurring in about one or two of every 10,000 IV injections of contrast agents.

However, there was no firm vote at the Monday's advisory committee meeting, and not every panelist agreed the black box should be no more.

What most panelists agreed on, however, was that the new data that have been collected since the addition of the black box in 2008 don't provide evidence the warning is too strict, nor do they provide evidence that the warning is not strict enough.

In other words, it appears that it was premature for the FDA to ask for guidance from the dual advisory committees when no new compelling data exist to change the status quo one way or the other.

"I did not see anything in the data that informed my judgment one way or the other," panelist Sanjay Kaul, MD, a cardiologist at Cedars-Sinai in Los Angeles told MedPage Today after the meeting. "If the FDA was asking us to change the box warning on the basis of the new data, I didn't see any new information to be actionable."

In fact, panelists' views on whether to scrap the box or keep it seemed to depend more on their view of black box warnings in general and less on data.

For instance, one panelist, Ralph D'Agostino, PhD, a statistician at Boston University, said, "Based on what I heard today, my feeling is that we don't have enough evidence to feel comfortable about any decision," and he recommended nixing the box.

Meanwhile, the consumer representative on the panel, Sidney Wolfe, MD, of the group Public Citizen, agreed there isn't any new evidence, but came to a different conclusion: That the box should stay because no new information exists to warrant lessening the warning.

A third panelist, Brian Strom, MD, director of the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania, agreed the data were lacking and said taking the black box away might send the wrong message.

"To take it away now sends a clear message that we've seen data that changes the risk/benefits, and we haven't," he said. "If we haven't seen anything to change it, [taking the box away] would send a clear message that these things are safe."

Currently, the agents contain boxed warnings of cardiopulmonary and hypersensitivity reactions with recommendations to monitor vital signs, cardiac rhythm, and oxygen saturation during and at least 30 minutes after administration, and to have equipment and trained personnel readily available for resuscitation. The box also warns that serious cardiopulmonary reactions, including fatalities, have occurred during or following administration of the agents.

The companies that make the agents, along with several panelists, said the presence of a black box deters physicians from using the agents, which is a detriment because they can make it easier to spot abnormalities such as tumors.

But an FDA presentation indicated that the box warning at first may have deterred use of the contrast agents, but use has since climbed back up to pre-black box levels.

Kaul said he wondered why the companies that make the agents only relied on pre-2008 data, which was from before the black box was implemented. If they had included later data, it might have been clearer to see what actual effect the box had on clinical usage of contrast agents.

The panel reviewed meta-analyses of more than 200,000 patients, which found that microbubble contrast agents used in echocardiography don't elevate cardiovascular risk.

It examined postmarketing data from Lantheus , the company that makes Definity, that showed a lower rate of heart attack among patients given the Definity contrast agent during echocardiography -- 0.15% compared with 0.2% among those with no contrast use.

"During the three years since the FDA requested postmarketing surveillance, there have been no significant changes to the Definity safety profile and the rate of adverse events has remained approximately the same since the last advisory committee meeting," the company said in a statement.

Postmarking safety studies conducted by GE Healthcare, the company that makes Optison, found no statistically significant risks, as well as no safety signals, in patients who were given their agent.

The advisory committee wasn't convinced that one agent was better than another, or that the studies proved either of the agents were safe, or that they are unsafe.

The FDA is not required to follow the advice of its advisory committees, but it often does.

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